Non-aqueous aerosol formulation comprising rosiglitazone maleate, a non-aqueous carrier, and an amino acid stabilizer

ABSTRACT

A non-aqueous medicinal aerosol formulation comprising rosiglitazone maleate, a fluid carrier, and an amino acid stabilizer. The aerosol formulation may also include drug combination formulations comprising rosiglitazone maleate and a second anti-diabetic medicament.

This application claims priority from U.S. provisional application Ser.No. 60/201,564 filed May 1, 2000, which is incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a medicinal aerosol formulation, and moreparticularly, to a medicinal aerosol formulation comprisingrosiglitazone maleate and a protective colloid stabilizer.

2. Description of the Related Art

Delivery of drugs to the lung by way of inhalation is an important meansof treating a variety of conditions, including such common localconditions as cystic fibrosis, pneumonia, bronchial asthma and chronicobstructive pulmonary disease and some systemic conditions includingpain management, immune deficiency, hormonal therapy, erythropoiesis,diabetes, etc. Anti-diabetic drugs, e.g. an insulin, are among the drugsthat are administered to the lung for such purposes. Such drugs arecommonly administered to the lung in the form of an aerosol of particlesof respirable size (less than about 10 μm in diameter). In order toassure proper particle size in the aerosol, particles can be prepared inrespirable size and then incorporated into a colloidal dispersioncontaining either a propellant, as a pressurized metered dose inhaler(MDI), or air such as is the case with a dry powder inhaler (DPI).Alternatively, formulations can be prepared in solution or emulsion formin order to avoid the concern for proper particle size in theformulation. Solution formulations must nevertheless be dispensed in amanner that produces particles or droplets of respirable size.

For MDI preparations, once prepared, the aerosol formulation is filledinto an aerosol canister equipped with a metered dose valve. In thehands of the patient the formulation is dispensed via an actuatoradapted to direct the dose from the valve to the patient.

What is needed and desired is a stable aerosol formulation for thetreatment of diabetes and conditions related thereto comprisingrosiglitazone maleate.

SUMMARY OF THE INVENTION

It has surprisingly been found that novel and stable medicinal aerosolformulations of rosiglitazone maleate can be obtained without the use ofeither cosolvents, such as ethanol, or surfactants, such as sorbitantrioleate which are typically added to a binary aerosol formulation.Such stable medicinal aerosol formulations are obtained by the use of aprotective colloid stabilizer.

DETAILED DESCRIPTION OF THE INVENTION

This application makes reference to U.S. application Ser. No. 09/158,369filed Sep. 22, 1998, now U.S. Pat. No. 6,136,294, which is issued onOct. 24, 2000 which is incorporated hereinto by reference in itsentirety.

This invention involves a stable suspension aerosol formulation suitablefor pressurized delivery which comprises (1) rosiglitazone maleate, (2)a suitable propellant, and (3) a suitable stabilizer.

Rosiglitazone maleate or any of its derivatives such as the maleate, isa suitable medicament or drug which is suitable for administration byinhalation, the inhalation being used for oral and nasal inhalationtherapy. A stable, colloidal dispersion of the medicament in a fluid,e.g. air, hydrocarbon gases, chlorofluorocarbon (CFC) propellants ornon-CFC propellants, such as tetrafluoroethane (HFA-134a) andheptafluoropropane (HFA-227) is described.

A stabilizer of a polyionic species, such as an amino acid and a smallmolecule peptide, as inactive formulation components which trigger lossof adhesive bond strength between the medicament particles is employed.An electret or sterially stabilized aerocolloid particles of theselected medicaments is thus formed. Electrets are the electrostaticequivalent of permanent magnets but can be susceptible to breakdown inthe presence of moisture, such as that present in air or at ambienthumidity conditions of the respiratory tract. Accordingly the presentinvention applies to dry powder aerosols, portable nebulizer systems, aswell pressurized metered dose inhaler formulations.

The resultant aerocolloid is chemically and physically stable and canremain in suspension until the particles of rosiglitazone maleate reachthe alveolar or other absorption sites in the airways of a patient, e.g.human, animal, being treated. Once at the absorption site, the particlesof rosiglitazone maleate should be efficiently trapped at the depositionsite as a result of moisture in the ambient, dissolve rapidly in theepithelial lining fluids, and be absorbed quickly across thebiomembranes of the patient, thereby limiting possible deactivation bymetabolizing enzymes in the airways.

Rosiglitazone maleate to which the subject invention is directed forms astable dispersion suitable for delivery to a patient, e.g., human oranimal. Rosiglitazone maleate alone can be delivered to the patient orit can be combined with another suitable anti-diabetic agent selectedfrom an acetohexamide, chlorpropamide, tolazemide, tolbutamide,glipizide, glyburide, glucophage, phentolamine, etc., and a mixture ofany two or three of the foregoing medicaments or other medicaments.Typically, additional medicaments combined with rosiglitazone, alone orcombined with another suitable anti-diabetic agent, include a peptide,polypeptide, or protein biotherapeutic ranging from 0.5 K Dalton to 150K Dalton in molecular size. In particular, the peptide, polypeptide, orprotein biotherapeutic medicament includes diabetic aids; insulins andinsulin analogs; amylin; glucagon; surfactants; immunomodulatingpeptides such as cytokines, chemokines, lymphokines, interleukins suchas taxol, interleukin-1, interleukin-2, and interferons; antibiotics andother antiinfectives; hormones and growth factors; enzymes; vaccines;immunoglobulins; vasoactive peptides; antisense agents; genes,oligonucleotides, and nucleotide analogs.

The term diabetic aid includes natural, synthetic, semi-synthetic andrecombinant medicaments such as activin, glucagon, insulin,somatostatin, proinsulin, amylin, and the like.

The term “insulin” shall be interpreted to encompass natural extractedhuman insulin, recombinantly produced human insulin, insulin extractedfrom bovine and/or porcine sources, recombinantly produced porcine andbovine insulin and mixtures of any of these insulin products. The termis intended to encompass the polypeptide normally used in the treatmentof diabetics in a substantially purified form but encompasses the use ofthe term in its commercially available pharmaceutical form, whichincludes additional excipients. The insulin is preferably recombinantlyproduced and may be dehydrated (completely dried) or in solution.

The terms “insulin analog,” “monomeric insulin” and the like are usedinterchangeably herein and are intended to encompass any form of“insulin” as defined above wherein one or more of the amino acids withinthe polypeptide chain has been replaced with an alternative amino acidand/or wherein one or more of the amino acids has been deleted orwherein one or more additional amino acids has been added to thepolypeptide chain or amino acid sequences which act as insulin indecreasing blood glucose levels. In general, the “insulin analogs” ofthe present invention include “insulin lispro analogs,” as disclosed inU.S. Pat. No. 5,547,929, incorporated hereinto by reference in itsentirety; insulin analogs including LysPro insulin and humalog insulin,and other “super insulin analogs”, wherein the ability of the insulinanalog to affect serum glucose levels is substantially enhanced ascompared with conventional insulin as well as hepatoselective insulinanalogs which are more active in the liver than in adipose tissue.Preferred analogs are monomeric insulin analogs, which are insulin-likecompounds used for the same general purpose as insulin such as insulinlispro i.e., compounds which are administered to reduce blood glucoselevels.

The term “amylin” includes natural human amylin, bovine, porcine, rat,rabbit amylin, as well as synthetic, semi-synthetic or recombinantamylin or amylin analogs including pramlintide and other amylin agonistsas disclosed in U.S. Pat. Nos. 5,686,411, and 5,854,215, both of whichare incorporated hereinto by reference in their entirety.

The term “immunomodulating proteins” include cytokines, chemokines,lymphokines complement components, immune system accessory and adhesionmolecules and their receptors of human or non-human animal specificity.Useful examples include GM-CSF, IL-2, IL-12, OX40, OX40L (gp34),lymphotactin, CD40, CD40L. Useful examples include interleukins forexample interleukins 1 to 15, interferons alpha, beta or gamma, tumournecrosis factor, granulocyte-macrophage colony stimulating factor(GM-CSF), macrophage colony stimulating factor (M-CSF), granulocytecolony stimulating factor (G-CSF), chemokines such as neutrophilactivating protein (NAP), macrophage chemoattractant and activatingfactor (MCAF), RANTES, macrophage inflammatory peptides MIP-1a andMIP-1b, complement components and their receptors, or an accessorymolecule such as B7.1, B7.2, ICAM-1, 2 or 3 and cytokine receptors. OX40and OX40-ligand (gp34) are further useful examples of immunomodulatoryproteins. Immunomodulatory proteins can for various purposes be of humanor non-human animal specificity and can be represented for presentpurposes, as the case may be and as may be convenient, by extracellulardomains and other fragments with the binding activity of the naturallyoccurring proteins, and muteins thereof, and their fusion proteins withother polypeptide sequences, e.g. with immunoglobulin heavy chainconstant domains. Where nucleotide sequences encoding more than oneimmunomodulating protein are inserted, they can for example comprisemore than one cytokine or a combination of cytokines andaccessory/adhesion molecules.

The term “interferon” or “IFN” as used herein means the family of highlyhomologous species-specific proteins that inhibit viral replication andcellular proliferation and modulate immune response. Interferons aregrouped into three classes based on their cellular origin andantigenicity, alpha-interferon (leukocytes), beta-interferon(fibroblasts) and gamma-interferon (immunocompetent cells). Recombinantforms and analogs of each group have been developed and are commerciallyavailable. Subtypes in each group are based on antigenic/structuralcharacteristics. At least 24 interferon alphas (grouped into subtypes Athrough H) having distinct amino acid sequences have been identified byisolating and sequencing DNA encoding these peptides. See also Viscomi,1996 Biotherapy 10:59-86, The terms “alpha.-interferon”, “alphainterferon”, “interferon alpha”, “human leukocyte interferon” and IFNare used interchangeably herein to describe members of this group. Bothnaturally occurring and recombinant alpha interferons, includingconsensus interferon such as that described in U.S. Pat. No. 4,897,471,the contents of which are incorporated hereinto by reference in itsentirety, may be used in the practice of the invention. Human leukocyteinterferon prepared in this manner contains a mixture of human leukocyteinterferons having different amino acid sequences. Purified naturalhuman alpha interferons and mixtures thereof which may be used in thepractice of the invention include but are not limited to Sumiferon RTMinterferon alpha-n1 available from Sumitomo, Japan; Welfferonginterferon alpha-n1 (Ins) available from Glaxo-Wellcome Ltd., London,Great Britain; and Alferon RTM interferon alpha-n3 available from thePurdue Frederick Co., Norwalk, Conn.

The terms “anti-proteases” and “protease-inhibitors” are usedinterchangeably and apply to synthetic, semi-synthetic, recombinant,naturally-occurring or non-naturally occurring, soluble or immobilizedagents reactive with receptors, or act as antibodies, enzymes or nucleicacids. These include receptors which modulate a humoral immune response,receptors which modulate a cellular immune response (e.g., T-cellreceptors) and receptors which modulate a neurological response (e.g.,glutamate receptor, glycine receptor, gamma-amino butyric acid (GABA)receptor). These include the cytokine receptors (implicated inarthritis, septic shock, transplant rejection, autoimmune disease andinflammatory diseases), the major histocompatibility (MHC) Class I andII receptors associated with presenting antigen to cytotoxic T-cellreceptors and/or T-helper cell receptors (implicated in autoimmunediseases) and the thrombin receptor (implicated in coagulation,cardiovascular disease). The list also includes antibodies whichrecognize self-antigens such as those antibodies implicated inautoimmune disorders and antibodies which recognize viral (e.g., HIV,herpes simplex virus) and/or microbial antigens.

The terms “hormones” and “growth factors” include hormone releasinghormones such as growth hormone, thyroid hormone, sourced from natural,human, porcine, bovine, ovine, synthetic, semi-synthetic, or recombinantsources. These also include somatostatin analogs such as octreotide(Sandostatin), medicaments for respiratory disorders (e.g., superoxidedismutase), RDS (e.g., surfactants, optionally including apoproteins),and the like.

Examples of biological molecules for which lead molecules can besynthesized and selected and combined with rosiglitazone maleate inaccordance with the invention include, but are not limited to, agonistsand antagonists for cell membrane receptors, neurotransmitters, toxinsand venoms, viral epitopes, hormones, opiates, steroids, peptides,enzyme substrates and inhibitors, cofactors, drugs, lectins, sugars,oligonucleotides, nucleic acids, oligosaccharides, lipids, proteins, andanalogs of any of the foregoing molecules.

The term “analog” refers to a molecule, which shares a common functionalactivity with the molecule to which it is deemed to be an analog andtypically shares common structural features as well.

The term “recombinant” refers to any type of cloned biotherapeuticexpressed in procaryotic cells or genetically engineered molecule, orcombinatorial library of molecules which may be further processed intoanother state to form a second combinatorial library, especiallymolecules that contain protecting groups which enhance thephysicochemical, pharmacological, and clinical safety of thebiotherapeutic agent.

The term “vaccines” refers to therapeutic compositions for stimulatinghumoral and cellular immune responses, either isolated, or through anantigen presenting cell, such as an activated dendritic cell, that isable to activate T-cells to produce a multivalent cellular immuneresponse against a selected antigen. The potent antigen presenting cellis stimulated by exposing the cell in vitro to a polypeptide complex.The polypeptide complex may comprise a dendritic cell-binding proteinand a polypeptide antigen, but preferably, the polypeptide antigen iseither a tissue-specific tumor antigen or an oncogene gene product.However, it is appreciated that other antigens, such as viral antigenscan be used in such combination to produce immunostimulatory responses.In another preferred embodiment, the dendritic cell-binding protein thatforms part of the immunostimulatory polypeptide complex is GM-CSF. In afurther preferred embodiment, the polypeptide antigen that forms part ofthe complex is the tumor-specific antigen prostatic acid phosphatase. Instill other preferred embodiments, the polypeptide antigen may be anyone of the oncogene product peptide antigens. The polypeptide complexmay also contain, between the dendritic cell-binding protein and thepolypeptide antigen, a linker peptide. The polypeptide complex maycomprise a dendritic cell-binding protein covalently linked to apolypeptide antigen, such polypeptide complex being preferably formedfrom a dendritic cell binding protein, preferably GM-CSF, and apolypeptide antigen. The polypeptide antigen is preferably atissue-specific tumor antigen such as prostatic acid phosphatase (PAP),or an oncogene product, such as Her2, p21RAS, and p53; however, otherembodiments, such as viral antigens, are also within the contemplationof the invention.

The term “immunoglobulins” encompasses polypeptide oligonucleotidesinvolved in host defense mechanisms such as coding and encoding by oneor more gene vectors, conjugating various binding moieties of nucleicacids in host defense cells, or coupling expressed vectors to aid in thetreatment of a human or animal subject. The medicaments included in thisclass of polypeptides include IgG, IgE, IgM, IgD, either individually orin a combination with one another.

For purposes of the formulations of rosiglitazone maleate of thisinvention, which are intended for inhalation into the lungs, themedicament or drug is preferably micronized whereby a therapeuticallyeffective amount or fraction (e.g., ninety percent or more) ofrosiglitazone maleate or its combination drug is particulate. Typically,the particles have a diameter of less than about 10 microns, andpreferably less than about 5 microns, in order that the particles can beinhaled into the respiratory tract and/or lungs.

The rosiglitazone maleate medicament is present in the inventiveformulations in a therapeutically effective amount, that is, an amountsuch that the drug can be administered as a dispersion, aerosol, viaoral or nasal inhalation, and cause its desired therapeutic effect,typically preferred with one dose, or through several doses. The drug istypically administered as an aerosol from a conventional valve, e.g., ametered dose valve, through an aerosol adapter also known as anactuator.

The term “amount” as used herein refers to a quantity or to aconcentration as appropriate to the context. The amount of a drug thatconstitutes a therapeutically effective amount varies according tofactors such as the potency of the particular drug, the route ofadministration of the formulation, and the mechanical system used toadminister the formulation. A therapeutically effective amount of aparticular drug can be selected by those of ordinary skill in the artwith due consideration of such factors. Generally a therapeuticallyeffective amount of rosiglitazone maleate will be from about 1 mg toabout 500 mg based on 100 parts by weight of the fluid or propellantselected.

A suitable fluid includes air, a hydrocarbon such as n-butane, propane,isopentane, etc. or a propellant. A suitable propellant is anyfluorocarbon, e.g. a 1-6 hydrogen containing flurocarbon (such asCHF₂CHF₂, CF₃CH₂F, CH₂F₂CH₃ and CF₃CHFCF₃), a perfluorocarbon, e.g. a1-4 carbon perfluorocarbon, (such as CF₃CF₃, CF₃CF₂CF₃); or any mixtureof the foregoing, having a sufficient vapor pressure to render themeffective as propellants. Some typical suitable propellants includeconventional chlorofluorocarbon (CFC) propellants, such as propellants11, 12 and 114 or a mixture thereof. Non-CFC propellants, such as1,1,1,2-tetrafluoroethane (Propellant 134a),1,1,1,2,3,3,3-heptafluoropropane (Propellant 227) or a mixture thereofare preferred. The fluid or propellant is preferably present in anamount sufficient to propel a plurality of the selected doses of drugfrom an aerosol canister when such is employed.

A suitable stabilizer is selected. A suitable stabilizer includes (1) anamino acid selected from (a) a monoamino carboxylic acid of the formula,H₂N—R—COOH (I), (b) a monoamino dicarboxylic acid of the formula,H₂N—R(COOH)₂ (II) and (c) a diamino monocarboxylic acid of the formula(H₂N)₂—R COOH (III), where R is a straight or branched alkyl radical offrom 1 to 22 carbon atoms, which can be mono or poly-substituted withmoieties such as sulfide (—S—), oxide (—O—), hydroxyl (—OH), amide(—NH), sulfate (—SO4); aryl of the formula

where X is hydrogen, halogen (F, Cl, BR, I), alkyl of 1 to 6 carbonatoms, alkoxy of 1 to 6 carbon atoms, hydroxy and nitro; andheterocyclic, such as thienyl, furyl, pyranyl, imidazolyl, pyrrolyl,thizolyl, oxazolyl, pyridyl, and pyrimidinyl compounds; (2) a derivativeof the amino acid selected from (a) acid addition salts of the aminogroup, obtained from inorganic acids, such as hydrochloric, hydrobromic,sulfuric, nitric, phosphoric, and perchloric acids, as well as organicacids, such as tartaric, citric, acetic, succinic, maleic, fumaric,oxalic acids; (b) amides of the carboxylic acid group, e.g., glutamine,di-peptides, e.g. salts and esters of oxidized and unoxidizedL-cysteinylglycine, gamma-L-glutamyl-L-cysteine,N-acetyl-L-cysteine-glycine, either conjugated, unconjugated orpolymeric forms of L-Gly-L-Glu and L-Val-L-Thr,L-aspartyl-L-phenylalanine, muramyl dipeptides, nutrients such asL-tyrosyl-L-tyrosine, L-alanyl-L-tyrosine, L-arginyl-L-tyrosine,L-tyrosyl-L-arginine, N-Cbz-L-Leu-L-Leu-OCH and its salts or esters,glycyl-glycine, N-acetyl-L-aspartate-L-glutamate (NAAG), etc.; andtripeptides, e.g. oxidized and unoxidizedgamma-L-glutamyl-L-cysteinylglycine; muramyl tripeptides, etc. (c)esters of the carboxylic acid group obtained from aliphatic straight orbranched chain alcohols of from 1 to 6 carbon atoms, e.g.L-aspartyl-L-phenylalanine methylester (Aspartame®), (3) an ether of anyof the foregoing; (4) a hydrate or semi-hydrate of any of the foregoingand (5) a mixture of the amino acid and the derivative of the aminoacid.

Suitable amino acids of the formula I include glycine, alanine, valine,leucine, isoleucine, leucylalanine, methionine, threonine, isovaline,phenylalanine, tyrosine, serine, cysteine, N-acetyl-L-cysteine,histidine, tryptophan, proline, and hydroxyproline, e.g. trans-4-hydroxyproline. Compounds of the formula II include, aspartic acid, andglutamic acid, compounds of the formula (III) include arginine,glutamine, lysine, hydroxylysine, ornithine, asparagine, and citrulline.

A fluid or aerosol formulation preferably comprises the protectivecolloid stabilizer in an amount effective to stabilize the formulationrelative to an identical formulation not containing the stabilizer, suchthat the drug does not settle, cream or flocculate after agitation soquickly as to prevent reproducible dosing of the drug. Reproducibledosing can be achieved if the formulation retains a substantiallyuniform drug concentration for about fifteen seconds to about fiveminutes after agitation.

For optimal functional and therapeutic performance of the aerosolformulation, either as a dry powder or as an aerosol suspension, thestabilizer is present either as a coarse carrier (e.g., 20-90 μm) or asa finely micronized powder, ≦10 μm in diameter. In either case,reproducible drug dosimetry is obtained without the need to qualify theinspiratory maneuver of the patient. Accordingly, excellent doseuniformity is obtained at tidal flows of up to 2 liters, or atinspiratory flow rates of as low as 15 liters per minute to about 90liters per minute.

The particular amount of stabilizer that constitutes an effective amountis dependent upon the particular stabilizer, the particular propellant,and on the particular drug used in the formulation. It is therefore notpractical to enumerate specific effective amounts for use with specificformulations of the invention, but such amounts can readily bedetermined by those skilled in the art with due consideration of thefactors set forth above. Generally, however, the stabilizer can bepresent in a formulation in an amount from about 0.001 parts per millionto about 200,000 parts per million, more preferably about 1 part permillion to about 10,000 parts per million, most preferably from about 10parts per million to about 5,000 parts per million of the totalformulation.

It has surprisingly been found that the formulation of the invention isstable without the necessity of employing a cosolvent, such as ethanol,or surfactants. However, further components, such as conventionallubricants or surfactants, cosolvents, ethanol, etc., can also bepresent in an aerosol formulation of the invention in suitable amountsreadily determined by those skilled in the art. In this regard,reference is made to U.S. Pat. No. 5,225,183, which is incorporatedhereinto by reference in its entirety.

Generally the formulations of the invention can be prepared by combining(i) the drug i.e. rosiglitazone maleate, in an amount sufficient toprovide a plurality of therapeutically effective doses; (ii) thestabilizer in an amount effective to stabilize each of the formulations;(iii) the fluid or propellant in an amount sufficient to propel aplurality of doses, e.g. from an aerosol canister; and (iv) any furtheroptional components e.g. ethanol as a cosolvent; and dispersing thecomponents. The components can be dispersed using a conventional mixeror homogenizer, by shaking, or by ultrasonic energy. The components canalso be dispersed using a bead mill or a microfluidizer. Bulkformulations can be transferred to smaller individual aerosol vials byusing valve to valve transfer methods, pressure filling or by usingconventional cold-fill methods. It is not required that a stabilizerused in a suspension aerosol formulation be soluble in the propellant.Those that are not sufficiently soluble can be coated onto the drugparticles in an appropriate amount and the coated particles can then beincorporated in a formulation as described above.

Aerosol canisters equipped with conventional valves, preferably metereddose valves, can be used to deliver the formulations of the invention.It has been found, however, that selection of appropriate valveassemblies for use with aerosol formulations is dependent upon theparticular stabilizer and other adjuvants used (if any), on thepropellant, and on the particular drug being used. Conventional neopreneand buna valve rubbers used in metered dose valves for deliveringconventional CFC formulations often have less than optimal valvedelivery characteristics and ease of operation when used withformulations containing HFC-134a or HFC-227. Therefore certainformulations of the invention are preferably dispensed via a valveassembly wherein the diaphragm is made of a nitrile rubber such asDB-218 (American Gasket and Rubber, Schiller Park, Ill.) or an EPDMrubber such as Vistalon™ (Exxon), Royalene™ (UniRoyal), bunaEP (Bayer).Also suitable are diaphragms fashioned by extrusion, injection moldingor compression molding from a thermoplastic elastomeric material such asFLEXOMER™ GERS 1085 NT polyolefin (Union Carbide).

Conventional aerosol canisters, coated or uncoated, anodized orunanodized, e.g., those of aluminum, glass, stainless steel,polyethylene terephthalate, and coated canisters or cans with epon,epoxy, etc., can be used to contain a formulation of the invention.

Conventional nebulizer systems can be employed with the formulations ofthis invention, as well as by powder aerosols.

The formulation of the invention can be delivered to the respiratorytract and/or lung by oral inhalation in order to effect bronchodilationor in order to treat a condition susceptible of treatment by inhalation,e.g., asthma, chronic obstructive pulmonary disease. The formulations ofthe invention can also be delivered by nasal inhalation in order totreat, e.g., allergic rhinitis, rhinitis, (local) or diabetes(systemic), or they can be delivered via topical (e.g., buccal)administration in order to treat, e.g., angina or local infection.

We claim:
 1. A nonaqueous medicinal aerosol formulation, whichcomprises: (a) a therapeutically effective amount of rosiglitazonemaleate; (b) a nonaqueous fluid propellant carrier for containing saidmedicament; and (c) a stabilizer selected from an amino acid, aderivative thereof, or a mixture of the foregoing.
 2. The formulation asdefined in claim 1 wherein said medicament is combined with a secondmedicament selected from the group consisting of an insulin analog, anamylin, an immunomodulating protein, an interleukin, an interferon, anerythropoietin, a heparin, a thrombolytic, an antitrypsin, ananti-protease, a hormone, a growth factor, an enzyme, a nucleic acid, animmunoglobulin, an antibiotic, an antiinfective, a calcitonin, ahematopoietic factor, a vaccine, a vasoactive peptide, an antisenseagent, an oligonucleotide, DNase, a cyclosporin, ribavirin or a mixtureof any of the foregoing medicaments.
 3. The formulation as defined inclaim 2 wherein said second medicament is selected from the groupconsisting of an insulin analog, an amylin, glucagon, octreotide,somatostatin, a calcitonin, an interferon, IgG, IgE, IgM, IgA, IgD, aninterleukin, a gene; a vector, glucagon, acetohexamide, chlorpropamide,tolazemide, tolbutamide, glipizide, glyburide, glucophage, phentolamine,an oligonucleotide, ribavirin or a mixture of any of the foregoingmedicaments.
 4. The formulation as defined in claim 1 which furtherincludes a cosolvent.
 5. The formulation as defined in claim 4 whereinsaid cosolvent comprises ethanol.
 6. A nonaqueous medicinal formulation,which consists essentially of: (a) a therapeutically effective amount ofrosiglitazone maleate combined with a second medicament selected fromthe group consisting of an insulin, an insulin analog, an amylin, animmunomodulating protein, an interleukin, an interferon, anerythropoietin, a heparin, a thrombolytic, an antitrypsin, ananti-protease, a hormone, a growth factor, an enzyme, a nucleic acid, animmunoglobulin, an antibiotic, an antiinfective, a calcitonin, ahematopoietic factor, a vaccine, a vasoactive peptide, an antisenseagent, an oligonucleotide, DNase, a cyclosporin, ribavirin, glucagon,octreotide, somatostatin, IgG, IgE, IgM, IgA, IgD, an interleukin, agene, a vector, acetohexamide, chlorpropamide, tolazemide, tolbutamide,glipizide, glyburide, glucophase, phentolamine or a mixture of any ofthe foregoing medicaments. (b) a nonaqueous fluid propellant carrier forcontaining said medicament; and (c) a stabilizer selected from an aminoacid, a derivative thereof, or a mixture of the foregoing.
 7. Theformulation as defined in claim 1 or claim 6 wherein said stabilizer isselected from the group consisting of the twenty essential andnonessential existing amino acids, any mixture thereof, and anyderivative of the foregoing.
 8. The formulation as defined in claim 1 orclaim 6 wherein said stabilizer is selected from the group consisting of(1) a di-peptide selected from the group consisting of a salt and anester of oxidized and unoxidized L-cysteinylglycine, gammaL-glutamyl-L-cysteine, N-acetyl-L-cysteine-glycine; (2) a conjugated,unconjugated or polymeric form-of L-Gly L-Glu and,L-Val-L-Thr; (3)L-aspartyl-L-phenylalanine; (4) a muramyl dipeptide; (5) a nutrientselected from the group consisting of L-tyrosyl-L-tyrosine,L-alanyl-L-tyrosine, L-arginyl-L-tyrosine, L-tyrosyl-L-arginine,N-Cbz-L-Leu-L-Leu-OCH and salts or esters of the foregoing; (6)glycylglycine; (7) N-acetyl-L-aspartate-L-glutamate; (NAAG) (8) atripeptide selected from the group consisting of an oxidized and anunoxidized form of gamma-L-glutamyl-L-cysteinylglycine or a muramyltripeptide and (9) a mixture of any of the foregoing stabilizers.
 9. Theformulation as defined in claim 1 or claim 6 wherein said fluid carrieris a propellant selected form the group consisting of1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane or a mixturethereof.
 10. The formulation as defined in claim 1 or claim 6 whereinsaid fluid carrier is a hydrocarbon propellant selected from the groupconsisting of n-butane, propane, isopentane or a mixture thereof. 11.The formulation as defined in claim 1 or claim 6 wherein saidrosiglitazone maleate is present in a therapeutic amount ranging from 1mg to 500 mg based on 100 parts by weight of the fluid carrier.
 12. Amethod of treating in a human or an animal a condition capable oftreatment by oral or nasal inhalation, which comprises, administering aformulation according to claim 1 or claim 6 to said human or animal byoral or nasal inhalation.
 13. A formulation according to claim 1 orclaim 6 in an aerosol canister equipped with a metered dose valve. 14.The formulation as defined in claim 1 or claim 6 wherein said stabilizeris present in an amount effective to prevent settling, creaming orflocculation of the formulation for a time sufficient to allowreproducible dosing of the drug after agitation of the formulation. 15.The formulation as defined in claim 14 wherein said stabilizer ispresent in an amount ranging from about 0.001 parts per million to about200,000 parts per million of the total weight of the formulation.
 16. Amethod of preparing a stable medicinal aerosol formulation according toclaim 1 or claim 6 which comprises: (a) combining (i) said rosiglitazonemaleate medicament in an amount sufficient to provide a plurality oftherapeutically effective doses, (ii) said fluid carrier in an amountsufficient to propel a plurality of said therapeutically effectivedoses; and (iii) said stabilizer in an amount effective to stabilize theformulation; and (b) dispersing components (i), (ii) and (iii).
 17. Themethod as defined in claim 16 wherein the medicinal aerosol formulationfurther comprises combining in step (a) a cosolvent and in step (b)dispersing components (i), (ii) and (iii) with said cosolvent.
 18. Amethod of stabilizing a nonaqueous suspension aerosol formulationcomprising a nonaqueous propellant and rosiglitazone maleate medicament,which comprises, incorporating into the formulation a stabilizerselected from the group consisting of a suitable amino acid, aderivative thereof, or any mixture of the foregoing, in an amount whichis effective to prevent settling, creaming, or flocculation of theformulation for a time sufficient to allow reproducible dosing of thedrug after agitation of the formulation.
 19. A metered dose inhalercontaining a nonaqueous medicinal aerosol formulation, the formulationcomprising: (a) a rosiglitazone maleate medicament in a therapeuticallyeffective amount; (b) a nonaqueous propellant; and (c) a suitablestabilizer selected from an amino acid, an amino acid derivative, or amixture of the foregoing, present in an amount sufficient to stabilizethe formulation to prevent settling, creaming or flocculation for a timesufficient to allow reproducible dosing of the drug after agitation ofthe formulation.
 20. The metered dose inhaler as defined in claim 19wherein the stabilizer is selected from the group consisting of thetwenty essential and nonessential existing amino acids, any mixture ofany of the foregoing and any derivative of the foregoing.
 21. Anonaqueous medicinal aerosol formulation, which consists essentially of:(a) a therapeutically effective amount of rosiglitazone maleate; (b) anonaqueous fluid carrier for containing said medicament; and (c) astabilizer selected from an amino acid, a derivative thereof, or amixture of the foregoing.